Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

Abstract

Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

Tetramethylpyrazine Alleviates Endothelial Glycocalyx Degradation and Promotes Glycocalyx Restoration via TLR4/NF-κB/HPSE1 Signaling Pathway During Inflammation

“…LPS acts as a pro-inflammatory substance to trigger an inflammatory response and induce monocyte into the endothelium, resulting in endothelial functional impairment (Park and Lee, 2013). LPS-induced glycocalyx damage has been a standard model of vascular injury (Liu et al, 2018;Wang et al, 2021). We evaluated the effect of LPS on glycocalyx integrity as endothelial inflammatory maker.…”

Endothelial glycocalyx in hepatopulmonary syndrome: An indispensable player mediating vascular changes

“…Besides, these studies also reveal that ROS and a series of sheddases such as heparanase, hyluronase, and MMPs are potential targets against pulmonary eGCX degradation. Much impressive results are from the studies of FGF, protectin conjugates in tissue regeneration 1 (PCTR1), maresin conjugates in tissue regeneration 1 (MCTR1), Colivelin and Fucoidan, which show the reconstitution effect on pulmonary eGCX via the signals of FGFR1/EXT-1, SIRT1/NF-κB p65/EXT-1, STAT3/AMPK, ANG2 respectively ( 61 , 63 , 152 – 154 ). Clinically, the aim of reconstituting eGCX should be emphasized in combination with the treatments of anti-inflammation and inhibition of ROS and sheddases provided that it is likely to preclude or delay the occurrence of vascular leakage and the consequent lung edema ( 136 , 158 ).…”

“…The damaged eGCX denudes the surface of vascular endothelial cells, facilitating excessive vascular permeability and leakage, and contributing to further pathological deterioration by causing interstitial edema (59,60). More importantly, the degradation of eGCX may be balanced by a dynamic reconstitution via the synthase exostosin (EXT), which warrants a relatively stable endothelial barrier despite the appearance of IPVD, and prevents extravasation of leukocytes and leakage of fluid and plasma proteins into the interstitial space (61)(62)(63)(64)(65). This may explain in part why HPS is not frequently complicated with pulmonary edema at an early stage (66).…”

Bazedoxifene activates the angiotensin II‑induced HUVEC hypertension model by targeting SIRT1

“…Cells in the treatment group were treated with bazedoxifene (2, 4, 6, 8 and 10 µM) for 1 h prior to AngII induction for 2 h ( 20 ). To block SIRT1, cells were incubated with 1 µM of the inhibitor EX527 for 48 h prior to bazedoxifene treatment ( 21 ). All drugs were purchased from Sigma-Aldrich, Merck KGaA.…”